Development of small molecules targeting the pseudokinase Her3

Sang Min Lim; Ting Xie; Kenneth D. Westover; Scott B. Ficarro; Hyun Seop Tae; Deepak Gurbani; Taebo Sim; Jarrod A. Marto; Pasi A. Jänne; Craig M. Crews; Nathanael S. Gray

doi:10.1016/j.bmcl.2015.04.103

Development of small molecules targeting the pseudokinase Her3

Sang Min Lim, Ting Xie, Kenneth D. Westover, Scott B. Ficarro, Hyun Seop Tae, Deepak Gurbani, Taebo Sim, Jarrod A. Marto, Pasi A. Jänne, Craig M. Crews, Nathanael S. Gray

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.

Original language	English (US)
Article number	22688
Pages (from-to)	3382-3389
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2015.04.103
State	Published - Jul 3 2015

Keywords

Cancer
Her3
Hydrophobic tagging
Pseudokinase
Pyrazolopyrimidine

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2015.04.103

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title = "Development of small molecules targeting the pseudokinase Her3",

abstract = "Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.",

keywords = "Cancer, Her3, Hydrophobic tagging, Pseudokinase, Pyrazolopyrimidine",

author = "Lim, {Sang Min} and Ting Xie and Westover, {Kenneth D.} and Ficarro, {Scott B.} and Tae, {Hyun Seop} and Deepak Gurbani and Taebo Sim and Marto, {Jarrod A.} and J{\"a}nne, {Pasi A.} and Crews, {Craig M.} and Gray, {Nathanael S.}",

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doi = "10.1016/j.bmcl.2015.04.103",

language = "English (US)",

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AU - Lim, Sang Min

AU - Xie, Ting

AU - Westover, Kenneth D.

AU - Ficarro, Scott B.

AU - Tae, Hyun Seop

AU - Gurbani, Deepak

AU - Sim, Taebo

AU - Marto, Jarrod A.

AU - Jänne, Pasi A.

AU - Crews, Craig M.

AU - Gray, Nathanael S.

PY - 2015/7/3

Y1 - 2015/7/3

N2 - Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.

AB - Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.

KW - Cancer

KW - Her3

KW - Hydrophobic tagging

KW - Pseudokinase

KW - Pyrazolopyrimidine

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ER -

Development of small molecules targeting the pseudokinase Her3

Abstract

Keywords

ASJC Scopus subject areas

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